This portion of the proposed work relates to characterization of small caliber nerve fibers in mouse footpads and will be performed at the Johns Hopkins School of Medicine in the Epidermal Nerve Fiber laboratory. In response to the RFA #DK 01-009, the consortium proposes to create and study new transgenic mouse models of diabetes. Current rodent models of diabetes fail to develop changes that closely resemble human diabetic neuropathy. The reasons for this are not fully understood, but may be attributed to the short lifespan of rodents that precludes complications of advanced disease, or perhaps to the absence of genetic-susceptibility genes. By developing transgenic animals that potential the cellular injury associated with diabetes, it is postulated that a more accurate mouse model of human diabetic neuropathy will be established. The Johns Hopkins Neurology role in this project will focus on the characterization of abnormalities in the small caliber cutaneous nerve fibers, which are appreciated to be prominently affected in diabetes. These nerve fibers are the distal-most terminals of sensory nerve and are therefore especially relevant to a length-dependent neuropathy such as diabetic polyneuropathy. Footpad biopsies from mice will be fixed, sectioned and immunohistochemically stained for the panaxonal marker PGP9.5 allowing quantitation of epidermal nerve fibers. The accessible location of epidermal nerve fibers has contributed to the evolution of skin biopsy technique as a robust, relatively non-invasive clinical and research tools with which to study small caliber nerve fibers in humans Cultivation of this technique in promising animal diabetic models will threefold hold relevance to human diabetic polyneuropathy.